The ability of memantine, a noncompetitive glutamatergic NMDA receptor antagonist of moderate affinity, to improve cognitive function in both animal models of human dementia and in patients with dementia of the AD type is well established. For example, in preclinical behavioral experiments using the water maze, this adamantane derivative (2 mg/kg) reverses scopolamine-induced learning deficits in mice (Dreyer B D, Anderson W G, Johnson H, O'Callaghan M, Seo S, Choi D Y, Riedel G, Platt B., “Memantine acts as a cholinergic stimulant in the mouse hippocampus”, J Alzheimer's Dis. 2007 December; 12(4): 319-33. Similarly, controlled clinical trials have demonstrated the ability of memantine to benefit cognition in those suffering from moderate to severe forms of AD (Grossberg G T, Pejovic V, Miller M L, Graham S M, Dement “Memantine therapy of behavioral symptoms in community-dwelling patients with moderate to severe Alzheimer's disease”. Geriatr Cogn Disord 2009; 27(2):164-172). These clinical trial results indicate that the antidementia efficacy and safety profile of memantine closely resemble those of donepezil and other approved ChEIs. Based on these findings in patients with moderate to severe AD, memantine has been approved for sale by regulatory authorities in the US and elsewhere for more than a decade.
More recently, memantine (usually 20 mg/day in an IR-unit form) has been reported to enhance the antidementia efficacy of ChEIs such as standard dose—usually 10 mg/day—donepezil (Tariot P N, Farlow M R, Grossberg G T, Graham S M, McDonald S, Gergel I—Memantine Study Group, “Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial”, JAMA 2004 Jan. 21; 291(3):317-324; Atri A, Molinuevo J L, Lemming O, Wirth Y, Pulte I, Wilkinson D, “Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy”, Alzheimers Res Ther. 2013 Jan. 21; 5(1):6). However, results from some randomized controlled trials in patients with moderate to severe AD have failed to show that the combination of donepezil plus memantine confers significant efficacy advantages over donepezil alone, regardless of whether donepezil was given at the standard 10 mg/day or the 23 mg/day dose (Porsteinsson A P, Grossberg G T, Mintzer J, Olin J T; Memantine MEM-MD-12 Study Group, “Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial”, Curr Alzheimer Res. 2008 February; 5(1):83-9; Doody R S, Geldmacher D S, Farlow M R, Sun Y, Moline M, Mackell J, “Efficacy and safety of donepezil 23 mg versus donepezil 10 mg for moderate-to-severe Alzheimer's disease: a subgroup analysis in patients already taking or not taking memantine”, Dement Geriatr Cogn Disord. 2012; 33(2-3):164-73; Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, O'Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P, “Donepezil and memantine for moderate to severe Alzheimer's disease”, N Engl J Med. 2012 Mar. 8.; 366(10):893-903).
Moreover, there is no generally accepted rationale for any symptomatic benefit gained by combining these drugs. Indeed, early on memantine was considered to act as an anticholinergic and thus with the potential of exacerbating AD symptoms (Lipton S A, Nature Reviews Drug Diiscovery 2006; 5:160), while later its cognitive benefits were often linked to its well established ability to inhibit NMDA receptor mediated glutamatergic mechanisms (Johnson J W, Glasgow N G, Povysheva N V, “Recent insights into the mode of action of memantine and ketamine”, Curr Opin Pharmacol 2015, February; 20:54-63).
Thus, to date, there is scant experimental support for this view and thus no basis to expect a synergistic or additive effect of memantine on cholinergic function. (Schmitt H P, “On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease”, Med Hypotheses. 2005; 65(2):259-65).
Conversely, it was established that the efficacy of the ChEI donepezil is improved by combining said donepezil with the nsPAChA solifenacin. In fact, for example, solifenacin is able to allow the increase up to 40 mg/day of donepezil daily dose in a human being, including a patients suffering from a dementia of Alzheimer type (Chase T N, Clarence-Smith K, “High Dose Cholinesterase Inhibitor Treatment of Alzheimer's Disease”—AAIC Poster Abstract #27291, 2015 [PI-290], Alzheimer's Association International Conference—2015, Jul. 24-28, Washington D.C.) In addition, said donepezil dose can also be further highly increased by increasing the dose of both solifenacin and donepezil, as illustrated in WO 2014/039627, the disclosure of which is incorporated herein in its entirety by reference.
The action of solifenacin high doses, i.e. of solifenacin doses that are at least as high as 10 mg, but also higher and even much higher, allow for an increase of the donepezil blood concentrations that are higher than those attained with donepezil alone and increase even further with increasing doses of solifenacin.
It is hereby specified that, in this disclosure and elsewhere in the scientific literature, donepezil, memantine and solifenacin are often cited as such, i.e. as the active molecules. In the pharmaceutical and medical field, these molecules are approved, sold, and used in form of a salt thereof, i.e. as donepezil hydrochloride, memantine hydrochloride and, respectively, solifenacin succinate (also designated “solifenacin compound with succinic acid 1:1” and the respective doses that are either administered in therapy or included in the respective commercial drugs are attributed to said salts.